Wilson - WTX101-301
Research type
Research Study
Full title
A Phase 3, Randomized, Rater-Blinder, Multi-Center Study to Evaluate the Efficacy and Safety of ALXN1840 Administered for 48 Weeks Versus Standard of Care in patients with Wilson Disease aged 12 years and Older with an Extension Period of up to 60 months
IRAS ID
239561
Contact name
Aftab Ala
Contact email
Sponsor organisation
Alexion Pharnaceuticals Inc
Eudract number
2017-004135-36
Duration of Study in the UK
1 years, 9 months, 27 days
Research summary
Wilson disease is a genetic disorder that causes copper (a mineral in your body) to build up in the liver and other tissues in your body, which can cause organs to not function properly. The liver acts like a copper storage, and the copper is effectively metabolised in healthy volunteers. However in patients with Wilson Disease, a mutation in the ATP7B gene prevents efficient production of the Copper transporter, ATPase2. This causes impaired incorporation of Copper in proteins designed to aid metabolism (enzymes) and impaired excretion of Copper, resulting in a build up of Copper.
The study drug, WTX101, is an investigational therapy being studied in the treatment of Wilson Disease. The study is being done to look at:
- How well WTX101 works compared to Standard of Care for Wilson Disease.
The study drug - 'WTX101' also know by its chemical name 'bis-choline tetrathiomolybdate' is copper-protein-binding agent. It is formulated as an enteric coated (gastro-resistant) tablet to be taken orally. It is noted that 'WTX101' works by actively removing Copper from the liver stores and detoxifying Copper through formation of complexes between the study drug, Copper and Albumin.
Approximately up to 102 patients will be enrolled in approximately 31 study centres across North America, and Europe including the UK. Patients will be randomised to either the Study drug or standard of care on 2:1 ratio, therefore participants will have a 66% chance of receiving the study drug and 33% chance of either continued standard of care (cohort 1) or initiating standard of care (cohort 2). The study is expected to last approximately 52 weeks.
Lay Summary will be available from this link:
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BdSeb2ygKkRC9r7htDbO3NAv5oA_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YLVniqbZAmQ0mA9RTTbj5d6pV3qW1GAlKZI1B5fKhu1BRPWryjl0uF3Ix4Y-2FRgtblQ1-2F802at5ikfyw3ryle2YPXLfN1rKZZOsvi9t6pL9pNka0Ghb4HZfHVX4pBC8Whi877xscWMMAdAtQcCx6hd47rubta1LLVeVzKW50ZHRvLw-3D-3D&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cafd6d8778f24495b7cdc08dc1c26c2dd%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638416200009408067%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=upF4%2FHeK25rIzCIz%2Fn4SOlevI%2FoBUzbwOx2l2DcyLXM%3D&reserved=0
Updated Lay Summary
Protocol, WTX101-
1 THANK YOU!
CLINICAL STUDY RESULTS STUDY IDENTIFICATION INFORMATION ALXN1840 formerly named WTX101 (trade name: not available)
A Phase 3, Randomized, Rater-Blinded, Multi-Center Study to Evaluate the Efficacy and Safety of ALXN1840 Administered For 48 Weeks Versus Standard of Care in Patients with Wilson Disease Aged 12 Years and Older With an Extension Period of Up To 60 Months United States, NCT03403205 | European Union, 2017-004135-36 | Protocol WTX101-301
Alexion would like to thank all of the participants, their families, and caregivers who took part in this clinical study. Taking part in studies like this one may contribute directly to the discovery of new treatments for people with Wilson Disease.
A Study to Learn If ALXN1840 is Considered Effective and Safe in Adults and Adolescents with Wilson Disease TREATMENTS STUDIED: STUDY TITLE: STUDY NUMBERS: Protocol, WTX101-301 United States, NCT03403205 European Union, 2017-004135-36 SPONSOR CONTACT INFORMATION: 1-888-765-4747 medinfo@alexion.com
2 Why was this study conducted?
Clinical studies, also called clinical trials, aim to answer questions about specific diseases or treatment procedures, and involve participants with medical conditions or healthy volunteers. Clinical studies to develop new treatments happen in four stages, from Phase 1 to Phase 4, each investigating specific questions about the treatment.
This was a Phase 3 study. Phase 3 studies look at the overall risks and benefits of a treatment compared to a placebo (a product similar in appearance to the treatment being tested but which contains no real medicine) or a control group (a group of participants who are not given the treatment in the study but serve as a reference).
In this study, a research drug called ALXN1840 was tested in adults and adolescents aged 12 years and older with Wilson Disease (WD). A research drug is a drug that is being tested to treat a certain condition but which has not yet received approval from the regulatory authorities for a prescribed treatment.
The researchers wanted to see how ALXN1840 affected the copper levels in the blood of participants with WD, compared to other existing treatments such as trientine, penicillamine, zinc, or a combination of these medicines. To do this, they measured a specific form of copper in the blood, called “directly measured non-ceruloplasmin-bound copper,” or dNCC. Ceruloplasmin is a protein that binds to copper and helps prevent it from building up in the body’s tissues.
Researchers also wanted to see if ALXN1840 was safe in participants with WD compared to other existing treatments.
What is WD?
WD is a rare genetic condition that prevents the body from removing extra copper, causing copper to build up in healthy organs and tissues.
Copper is a metal that is needed in the body in small amounts. Normally, the liver removes the extra copper with the help of a protein called ATP7B. In people with WD, the body does not produce enough ATP7B. As a result, copper builds up in healthy organs and tissues, such as the liver, eyes, and the brain, causing damage and affecting their functioning.
3 What are the symptoms of WD?
People with WD can experience many types of symptoms, including neurological symptoms (such as shaking hands, trouble with handwriting, and difficulty focusing). Some patients may experience liver failure (their liver no longer works) because of WD. These people may show signs of liver damage such as a yellowing of the skin and the whites of the eyes (jaundice).
Sometimes, people with WD have dark rings that appear to encircle the iris (the colored part of the eye), called Kayser–Fleischer rings. Some people with WD may only show abnormal blood test results that indicate liver disease. Diagnosis is based on signs and symptoms, an eye exam, laboratory tests, a liver biopsy, and genetic testing.
What treatments are available for WD?
Current treatments for WD include:
• Penicillamine and trientine, which are medications used to bind and remove copper from the body. • Zinc, a mineral that reduces the uptake of copper from food.
These medications are life-long treatments meant to be taken frequently (more than once a day), on an empty stomach.
ALXN1840 is an experimental medicine that specifically binds to the copper present in the blood and tissues.
4 What were the treatments researched in this study?
Participants were split into 2 groups:
• Group 1: Participants who had received other existing treatments for WD (trientine, penicillamine, zinc, or a combination of these medicines) for longer than 28 days before enrolling in the study
• Group 2: Participants who had never received any treatment for WD or who had received other existing treatments (trientine, penicillamine, zinc, or a combination of these medicines) for 28 days or fewer before enrolling in the study
Participants received a drug called ALXN1840 or other existing treatments for WD. ALXN1840 was given as tablets to be swallowed on an empty stomach.
Participants were ”randomized’’ (assigned by chance) to either ALXN1840 or other existing treatments for WD during the Treatment Period. Twice as many participants received ALXN1840 compared to other WD treatments.
Participants assigned to ALXN1840 received a dose of ALXN1840 ranging from 15 milligrams (mg) every other day to 60 mg once daily.
Participants assigned to ALXN1840 who were receiving penicillamine or trientine, and/or zinc for WD stopped taking these medications at least 48 hours before the beginning of the Treatment Period. The study had 2 periods:
• Treatment Period: Participants received the assigned treatments for 48 weeks.
• Extension Period: Participants could continue the treatment for up to 60 months. During the Extension Period, all participants received ALXN1840.
This study was “rater-blind”, which means that the people who performed the neurologic tests did not know which treatment was received.
Participants, participants’ caregivers, and study doctors knew which treatment participants received.
5 TREATMENT PERIOD
(Day 1 to week 48)
Group 1 Previous WD treatment received for longer than 28 days ALXN1840 Other WD treatment ALXN1840 Randomization
Group 2 Previous WD treatments received for 28 days or fewer / no previous WD treatment Day 1 EXTENSION PERIOD (Up to 60 months) 2:1 Week 48 60 months
6 Who could take part in this study?
To be able to take part in the study, participants had to meet the following requirements: Individuals were unable to take part if study doctors determined they had certain types and stages of liver damage (such as advanced liver scarring known as decompensated cirrhosis) or infections, or other medical conditions that could interfere with the understanding of the study results. Participants consented to be in the study. A parent or guardian provided consent for participants who were under 18 years of age. Where applicable, children and young adults under 18 years of age could also provide their assent to participate in this study. Male or female individuals aged 12 years or older Confirmed diagnosis of WD
7 88 women + 119 men = 207 participants
How many participants took part in this study?
Participants were between 12 and 72 years of age at the start of the study.
A total of 18 participants were younger than 18 years old. The study started in February 2018 and ended in June 2023.
WHERE WAS THIS STUDY DONE?
The study took place in 52 study centers in 22 countries across Austria, Australia, Canada, the Czech Republic, Denmark, France, Germany, Hong Kong, Hungary, Israel, Japan, New Zealand, Poland, Russia, Serbia, Singapore, South Korea, Spain, Taiwan, Turkey, the United Kingdom, and the United States.
8 WHAT WERE THE RESULTS OF THIS STUDY?
The researchers wanted to see how ALXN1840 affected the directly-measured non-ceruloplasmin bound copper (dNCC) in the blood of participants with WD, compared to other existing treatments such as trientine, penicillamine, zinc, or a combination of these medicines.
They also wanted to see if ALXN1840 was safe in participants with WD compared to other existing treatments. How did ALXN1840 affect total dNCC amounts compared with other WD treatments over 48 weeks ?
Researchers observed a greater difference in the amounts of dNCC in the blood in participants who received ALXN1840 compared to those who received other treatments.
The difference in the amounts of dNCC was more noticeable in Group 2 participants than in Group 1.
GROUP 1 Average difference in dNCC amounts from 0 to 48 weeks Group 1: Previous WD treatment received for longer than 28 days dNCC= directly measured non-ceruloplasmin-bound copper ALXN1840 Other WD treatments 2.5 0.87 GROUP 2 Average difference in dNCC amounts from 0 to 48 weeks
Group 2: Previous WD treatments received for 28 days or fewer / no previous WD treatment ALXN1840 Other WD treatments 4.76 0.96.
9 What were the safety findings in this study?
A side effect is any symptom a participant has during the study which may or may not be related to the study treatment.
Related side effects are unwanted medical events that happen during the study, and are considered to be related to the study treatment. Side effects are classified as either “mild”, “moderate”, or “severe” in intensity.
A serious side effect is thought to be an important medical event (e.g., requires a person to be admitted to the hospital, is life-threatening, causes disability, or causes death).
Side effects can vary from person to person. Researchers keep a record of all the side effects participants have when new treatments are studied. This helps determine which side effects occur as a result of the study treatment and which occur by chance or because of the participant’s underlying disease.
What serious side effects did participants have in this study?
Treatment Period: Overall, a total of 18 out of 137 (13.1%) participants who received ALXN1840 and 6 out of 70 participants (8.6%) who received other WD treatments had serious side effects.
A total of 2 out of 137 participants (1.5%) who received ALXN1840 experienced serious side effects that were thought by study doctors to be related to ALXN1840.
Extension Period: Overall, 44 out of 197 participants (22.3%) had serious side effects.
A total of 5 out of 197 participants (2.5%) experienced serious side effects that were thought by study doctors to be related to ALXN1840.
Serious side effects related to the study treatments are shown below.
10 A total of 2 out of 207 participants (1.0%) died during the Treatment Period due to side effects considered not to be related to the study drug.
One out of 197 participants (0.5%) died during the Extension Period due to side effects considered not to be related to the study drug. Leukopenia (low levels of white blood cells)
0 0 Extension Period ALXN1840 (197 participants)
Other WD treatments (70 participants)
Overall Study (Treatment Period + Extension Period) 1 (0.7%)
Treatment Period ALXN1840 (137 participants) 1 (0.7%) 0 0 Paranoia (a mental disorder in which a person has an extreme fear and distrust of others) Hepatic failure (when the liver doesn’t work well) 0 0 1 (0.5%) Herpes simplex hepatitis (inflammation of the liver because of a viral infection) 0 0 1 (0.5%) Increased level of ALT (alanine aminotransferase, a liver enzyme) in the blood (may be a sign of liver damage) 0 0 1 (0.5%) Hepatic enzyme increased (liver enzyme, may be a sign of liver damage) 0 0 1 (0.5%) Neurological symptom (symptoms related to the brain/ and or nerves) 0 0 1 (0.5%) 11 What side effects did participants have in this study? Treatment Period: Overall, 119 out of 137 participants (86.9%) who received ALXN1840 and 53 out of 70 participants (75.7%) who received other WD treatments had side effects. A total of 55 out of 137 participants (40.1%) who received ALXN1840 had a side effect that was thought by the study doctor to be related to ALXN1840.
Extension Period: Overall, 169 out of 197 participants (85.8%) had side effects. A total of 63 out of 197 (32%) had a side effect that was thought by the study doctor to be related to ALXN1840. The most common side effects related to study treatments, which happened in 2 or more participants in the study, are shown below: Neutropenia (low levels of neutrophils, a type of white blood cell) 2 (2.9%) 7 (3.6%) Extension Period ALXN1840 (197 participants)
Other WD treatments (70 participants) Overall Study (Treatment Period + Extension Period) 5 (3.6%) Treatment Period ALXN1840 (137 participants) Anemia (low levels of red blood cells) 2 (1.5%) 0 0 Leukopenia (low levels of white blood cells) 2 (1.5%) 2 (2.9%) 2 (1%) Thrombocytopenia (low levels of blood platelets) 0 0 3 (1.5%) Nausea (feeling like vomiting) 5 (3.6%) 0 2 (1%) Fatigue (excessive tiredness) 4 (2.9%) 0 0 Hepatic function abnormal (when the liver doesn’t work normally) 4 (2.9%) 0 0 Tremor (involuntary shaking) 4 (2.9%) 0 2 (1%) Rash (an area of red or swollen skin) 2 (1.5%) 0 0 Pruritus (itchiness) 4 (2.9%) 0 0 Acne (a skin condition similar to pimples) 2 (1.5%) 0 0 Neurological symptom (symptoms related to the brain/and or nerves) 0 0 2 (1%) Anxiety (feelings of uneasiness) 0 0 2 (1%)
12 Were there any other important safety findings in this study?
During the Treatment Period, 7 out of 137 participants (5.1%) stopped taking ALXN1840 because of side effects.
During the Extension Period, a total of 14 out of 197 participants (7.1%) stopped taking ALXN1840 because of side effects.
The most common side effect that caused the study doctor to stop treatment in these participants during both the Treatment Period and the Extension Period was increased levels of ALT in the blood, which may be a sign of liver damage.
13 OUTCOME OF THE STUDY
How has this study helped participants and researchers?
The information collected in this study showed that ALXN1840 bound more copper in the blood than other existing treatments for WD.
Most side effects were mild and thought by study doctors to be not related to ALXN1840.
Based on the results of other studies on ALXN1840 and discussions with regulatory authorities, Alexion has decided to stop researching ALXN1840 for the treatment of WD.
www.clinicaltrials.gov Use the study number NCT03403205 to search for more information on this website. Useful clinical study websites
This document provides a summary of the main results of the study. It includes information about the side effects that happened to participants in the study and the results of the questions the researchers wanted to answer. This summary was reviewed for readability by a patient advocacy group.
Complete study results are available to read at the following clinical study register(s):
Before a treatment can be approved for patients to use, researchers look at the results of many studies to decide which treatments work best and are safe. If you have any questions about ALXN1840 or your treatment of WD, please talk to your doctor.
You should not change your treatment based on the results of this study without talking to a doctor first. ALXN1840 is an experimental drug, and its development will not be continued.
ALXN1840 has not received approval from the regulatory authorities.
www.clinicaltrialsregister.eu Use the study number 2017-004135-36 to search for more information on this website.
14 Further studies Based on Phase II mechanistic studies and discussions with regulatory authorities, Alexion has decided to discontinue the ALXN1840 Clinical Program in WD.
A mechanistic clinical study is designed to understand the way an experimental medicine works and includes participants who may be on the study drug, a comparator drug, or placebo.
A global registry is ongoing. The “Natural History of WD” registry is a program that collects information on patients with WD. Please follow the link below to find out more details about the WD registry:
• Natural History of WD – Patient Registry 15 March 2024 | This summary includes known facts as of the time the document was finalized.
Natural History of WD – Patient RegistryREC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
18/EM/0039
Date of REC Opinion
15 Mar 2018
REC opinion
Further Information Favourable Opinion